DESCRIPTION: Neural plasticity, which has been demonstrated in the central auditory system, may be manifested by changes in synaptic efficacy via alterations in neurotransmitter systems, or by changes in synaptic arrangement, via reorganization of afferent and efferent pathways. A better understanding of the neurochemical mediators of auditory plasticity may lead to the development of novel therapeutic strategies for modulation of plastic changes that occur in response to deafness. To gain such an understanding is the long-term goal of this revised application. Evidence exists to support a role for the excitatory neurotransmitter, glutamate, and the intracellular signaling molecule, protein kinase C (PKC), as mediators of plasticity in central sensory pathways, including the auditory system. The experiments proposed in this application will further define how these signaling pathways may interact in central auditory pathways following deafferentation. Using immunocyto- chemistry, the pattern of expression of two isoforms of protein kinase C will be mapped in intact rat brain (Specific Aim 1). To determine the changes in expression of six isoforms of PKC in response to unilateral cochlear deafferentation, immunocyto- chemistry, immunoblotting, and in situ hybridization will be used to determine levels and patterns of distribution of protein and mRNA in the dorsal cochlear nucleus and auditory cortex at 0, 1, 2, 4, 7, 14, 28, 56, and 112 days post-lesion (Specific Aim 2). Finally, double-label immunocytochemistry for PKC isoforms and glutamate receptor subtypes/subunits will be used to characterize colocalization of isoforms of PKC with glutamate receptor subunits in the auditory cortex (Specific Aim 3). These studies should extend our knowledge of auditory synaptic plasticity at the molecular level and enhance our understanding of patterns of organization and reorganization in auditory pathways following injury to the auditory system. It is anticipated that this knowledge will facilitate the development of novel therapeutic strategies, and may facilitate the development of auditory prostheses, as it should improve our understanding of how the brain reorganizes in response to deafness.